Ling et al. provided a longitudinal multiomic view of human glioblastoma (GBM) evolution under intratumoral oncolytic viral therapy (CAN-3110), demonstrating the feasibility and importance of serial tumor sampling in studying therapeutic response. Spatial and temporal remodeling of the tumor microenvironment was mapped across 86 serial GBM biopsies from two patients. Multiomic analysis revealed therapeutic response, longitudinal and spatial reshaping of the tumor, expansion of HSV-reactive and tumor-specific T cell clonotypes, and enhanced HLA and cancer testis antigen presentation, despite indications of disease progression by MRI.
Contributed by Shishir Pant
ABSTRACT: Recurrent glioblastoma (rGBM) remains incurable. One barrier to the development of effective rGBM therapies is the difficulty in collecting posttreatment tumor tissue. Serial multiomic assays from longitudinal rGBM biopsies may uncover tumor responses to a treatment. Here, we obtained 97 serial rGBM biopsy cores over 4 months from the first two patients participating in a clinical trial of repeated intratumoral dosing of the immunotherapeutic agent CAN-3110. Multiomic analysis of the biopsy cores revealed therapeutic effects, including longitudinal and spatial reshaping of the rGBM's microenvironment, expansion of new T cell tissue-resident effector memory clonotypes against CAN-3110 epitopes and other undetermined antigens, and expression of human leukocyte antigen (HLA)-presented immunopeptides, including cancer testis antigens. Moreover, serial integrated multimodal analyses provided evidence of therapeutic responses to CAN-3110 despite traditional magnetic resonance imaging indicating progression. Clinically, the two treated patients achieved a pathologic response or stable clinical disease, respectively. These results show the value of longitudinal tissue sampling to understand rGBM's evolution during administration of an investigational therapy.
Author Info: (1) Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery and Center for Tumors of the Nervous System, Mass General Brigham Cancer Institute and Harvard Medical Sc
Author Info: (1) Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery and Center for Tumors of the Nervous System, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (2) Surgical Brain Mapping and Molecular Imaging Laboratory, Department of Neurosurgery, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (3) Department of Pathology, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. Department of Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (4) James P. Allison Institute, University of Texas MD Anderson Cancer Hospital, Houston, TX 77030, USA. (5) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (6) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (7) Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery and Center for Tumors of the Nervous System, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (8) Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery and Center for Tumors of the Nervous System, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (9) Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery and Center for Tumors of the Nervous System, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (10) Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery and Center for Tumors of the Nervous System, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (11) Surgical Brain Mapping and Molecular Imaging Laboratory, Department of Neurosurgery, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (12) Surgical Brain Mapping and Molecular Imaging Laboratory, Department of Neurosurgery, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (13) Department of Pathology, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. Department of Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (14) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (15) Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (16) Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery and Center for Tumors of the Nervous System, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. Department of Pathology, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (17) Surgical Brain Mapping and Molecular Imaging Laboratory, Department of Neurosurgery, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Broad Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Department of Neurology and Neurosurgery, McGill University, Montreal, QC H3AOG4, Canada. (18) Department of Pathology, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. Department of Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (19) Department of Pathology, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. Department of Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (20) Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (21) James P. Allison Institute, University of Texas MD Anderson Cancer Hospital, Houston, TX 77030, USA. (22) James P. Allison Institute, University of Texas MD Anderson Cancer Hospital, Houston, TX 77030, USA. (23) Department of Radiation Oncology, University of Texas MD Anderson Cancer Hospital, Houston, TX 77030, USA. (24) Department of Pathology, Johns Hopkins University Medical Center, Baltimore, MD 21205, USA. (25) Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (26) Department of Neurosurgery, University of Texas MD Anderson Cancer Hospital, Houston, TX 77030, USA. (27) Department of Neuro-Oncology, University of Texas MD Anderson Cancer Hospital, Houston, TX 77030, USA. (28) Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (29) Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (30) Department of Neurology, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (31) Division of Neuro-Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Medical Center, Baltimore, MD 21205, USA. (32) Department of Neurosurgery, Johns Hopkins University Medical Center, Baltimore, MD 21205, USA. (33) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (34) Department of Pathology, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. Department of Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (35) Department of Biostatistics, University of Texas MD Anderson Cancer Hospital, Houston, TX 77030, USA. (36) Candel Therapeutics Inc., Needham, MA 02494, USA. Accelerating GBM Therapies TeamLab, Cambridge, MA 02142, USA. (37) James P. Allison Institute, University of Texas MD Anderson Cancer Hospital, Houston, TX 77030, USA. Department of Immunology, University of Texas MD Anderson Cancer Hospital, Houston, TX 77030, USA. (38) Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. (39) Department of Pathology, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. Department of Pathology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (40) Surgical Brain Mapping and Molecular Imaging Laboratory, Department of Neurosurgery, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (41) Center for Neuro-Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (42) Broad Institute, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02115, USA. (43) Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery and Center for Tumors of the Nervous System, Mass General Brigham Cancer Institute and Harvard Medical School, Boston, MA 02115, USA.
